CN1138545C - 用于治疗人类疱疹-病毒-8的喷昔洛韦(Penciclovir)的应用 - Google Patents

用于治疗人类疱疹-病毒-8的喷昔洛韦(Penciclovir)的应用 Download PDF

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CN1138545C
CN1138545C CNB961937939A CN96193793A CN1138545C CN 1138545 C CN1138545 C CN 1138545C CN B961937939 A CNB961937939 A CN B961937939A CN 96193793 A CN96193793 A CN 96193793A CN 1138545 C CN1138545 C CN 1138545C
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K·M·爱斯瑟尔
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R·A·维雷霍格
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Abstract

分子式(A)化合物或生物前药、或药物上可接受的盐、磷酸酯和/或上述任何一种物质的酰基衍生物在制备用于治疗(包括预防)HHV-8感染的药物中的应用。

Description

用于治疗人类疱疹-病毒-8的 喷昔洛韦(Penciclovir)的应用
本发明涉及与感染人类疱疹病毒8(HHV-8)有关的疾病的治疗,并且涉及在制备用于治疗这类疾病的药物中化合物的应用。
此处所说的“治疗”包括适当的预防。
EP-A-141927(Beecham小组p.l.c.)公开了喷昔洛韦分子式为(A)的化合物:
Figure C9619379300041
及其盐、磷酸酯和酰基衍生物,作为抗病毒剂。喷昔洛韦的钠盐水合物公开在EP-A-216459(Beecham小组p.l.c.)中。喷昔洛韦及其抗病毒活性.也公开在摘要P.V11-5 P.193,‘第十四次微生物国际会议的摘要’,曼彻斯特,英格兰,1986年9月7-13日(Boyd等人)。
分子式(A)的化合物的口服活性生物前药是分子式(B):
Figure C9619379300042
以及在分子式(A)下定义的盐及其衍生物;其中X是C1-6烷氧基、NH2或氢。其中X是C1-6烷氧基或NH2的分子式(B)的化合物公开在EP-A-141927,其中X是氢、公开在EP-A-182024(Beecham小组p.l.c.)中的分子式(B)的化合物是优选的药物前体。分子式(B)的化合物的特别优选的例子是那些其中的X是氢,两个羟基为乙酰基形式的衍生物,在EP-A-182024的实例2中描述,在下文称之为泛昔洛韦(famciclovir)。
据报导,分子式(A)和(B)的化合物及其盐类和衍生物在治疗由疱疹病毒例如疱疹单-型1、疱疹单-型2、水痘-带状疱疹、EB病毒以及细胞巨化病毒所引起的感染时可能有效。泛昔洛韦,在英国和美国以商品名FAMVIR出售,用于治疗带状疱疹(带形疱疹)。
疱疹病毒8(HHV-8)是最近发现的人类疱疹病毒科的一员。此病毒由Chang等人在‘科学’(Science)Vol 266,1994年12月16日,p1865中首次报导,由Schulz等人在‘自然’(Nature)Vol 373,1995年1月5日,p17中命名为HHV-8。这种病毒在那里被描述为与卡波济肉瘤(KS)有关,卡波济肉瘤是患有获得性免疫缺陷综合症(AIDS)的人中最常发生的肿瘤。以前怀疑引起KS的病原体包括细胞巨化病毒(CMV)、肝炎B病毒、人类疱疹病毒6、HIV和穿透枝原体(Mycoplasma penetrans)。HHV-8与其它增生疾病相联系也是可能的。这些疾病涉及各种细胞类型,包括内皮的、上皮的、神经元的、胰腺的、骨髓细胞类型以及炎性的、自动免疫类的、以及组织变性的疾病例如类风湿关节炎、红斑狼疮(lupus eritematosis)以及多种硬化症。HHV-8与AIDS相关的疾病的相联系也是可能的。当用于本文时,包括用于HHV-8的另一个术语,即与卡波济肉瘤相联系的疱疹病毒。
现已发现上述化合物具有潜在的抗HHV-8的活性。
因此,本发明提供了一种用于治疗人类感染HHV-8的方法,此方法包括给需要这种治疗的人服用有效量的分子式(A)的化合物:
Figure C9619379300051
或生物前药,或者药物上可接受的盐、磷酸酯和/或者上述任何一种物质的酰基衍生物。
术语酰基衍生物用于本文包括存在一个或多个酰基的分子式(A)化合物的任何衍生物。除了那些本身具有生物活性的衍生物之外,还包括作为分子式(A)化合物的生物前药的衍生物。
分子式(A)化合物的形式是在EP-A-216459(Beecham小组p.l.c.)中公开的形式中的一种。
生物前药、药物上可接受的盐及衍生物的例子如上述欧洲专利参考文献中所述,本文引用其主要内容作为参考。
感兴趣的特别的分子式(B)化合物是9-(4-乙酸基-3-乙酸基甲基-丁基-1)-2-氨基嘌呤,已知为泛昔洛韦(FCV),吸收好的喷昔洛韦(PCV)的口服剂型。
分子式(A)化合物、生物前药、盐及其衍生物可如上面提到的欧洲专利参考文献所述制备。
化合物,特别是泛昔洛韦可以以口服形式给病人用药并且可以以糖浆、药片或胶囊的形式合成。当以药片的形式合成时,可以使用任何适用于配制这种固体组合物的药物用载体,例如,硬脂酸镁、淀粉、乳糖、葡萄糖、米、面粉及白垩。化合物也可以是可食入胶囊的形式,例如用于包装化合物的明胶形式,或者是糖浆、溶液或悬浮液的形式。合适的药用载体包括乙醇、丙三醇、盐水以及水,可以在其中加入香味剂或着色剂形成糖浆。
对于非肠道用药,制备含化合物和无菌载体的流体单位剂量型。化合物可以是悬浮的或溶解的,这决定于所用的载体和所需的浓度。非肠道用溶液通常用下述方法制备:首先将化合物溶于载体中并将其过滤灭菌,然后将其装入合适的小瓶和针剂瓶中并加以密封。有利地,辅药例如局部麻醉剂、保存剂和缓冲剂也溶入载体中。为了增强稳定性,在组合物装入小瓶并且在真空下除去水后,将组合物冷冻起来。
非肠道悬浮液以基本上相同的方法制备,所不同的只是将化合物悬浮在载体中而不是将其溶解,并且在悬浮在无菌载体中之前先通过暴露在环氧乙烷下以进行灭菌。有利地,在组合物中包括表面活性剂或润湿剂以促进本发明化合物的均匀分布。
优选的非肠道剂型包括水溶液剂型,用消毒的水或生理盐水,其pH值大约为7.4或更大,特别是,含喷昔洛韦钠盐水合物。
在普通实践中,组合物通常应带有用于有关治疗的书写或印刷的用法说明。
治疗病毒感染的有效量取决于感染的性质和严重性以及哺乳动物的体重。
合适的剂量单位可以含50mg~5g的有效组分,例如100mg~2g,例如100~500或1500mg。这种剂量可以是一天用药1~4次或更普通地为一天2或3次。通常,化合物的有效剂量的范围为0.2~40mg/kg体重/天或更普通地为10~20mg/kg/天。就泛昔洛韦而论,剂量单位是125mg、250mg、500mg、750mg、1000mg、1250mg或1500mg。
在合适的剂型中,喷昔洛韦也可以例如作为乳膏剂局部用药。
本发明也提供了用于治疗HHV-8感染的药品的制备中下列化合物的用法:分子式(A)化合物或生物前药,或药物上可接受的盐、磷酸酯和/或上述任何一种物质的酰基衍生物。这类治疗可以按上文所述的方法进行。
本发明进一步提供了用于治疗HHV-8感染的药用组合物,这种药用组合物包含有效量的分子式(A)化合物或生物前药、或药物上可接受的盐、磷酸酯和/或上述任何一种物质的酰基衍生物以及药物上可接受的载体。这种组合物可按如下文所述的方法制备。
分子式(A)化合物与其药物前体与干扰素共同显示了协同的抗病毒作用;使用含这两个组分的组合产品,按照相同或不同的途径进行有序的或伴随的用药治疗因此在本发明的范围内。这类产品在EP-A-271270(Beecham小组p.l.c.)中描述,结合其它免疫调节化合物例如其它细胞因子或细胞因子诱导剂,或其它激发或抑制免疫应答的化合物也在本发明的范围内。

Claims (6)

1.分子式(A)化合物或生物前药、或药物上可接受的盐、磷酸酯和/或上述任何一种物质的酰基衍生物在制备用于治疗(包括预防)HHV-8感染的药物中的应用,所述分子式(A)为:
2.分子式(A)化合物或生物前药、或药物上可接受的盐、磷酸酯和/或上述任何一种物质的酰基衍生物在制备用于治疗(包括预防)卡波济肉瘤的药物中的应用,所述分子式(A)为:
3.分子式(A)化合物或生物前药、或药物上可接受的盐、磷酸酯和/或上述任何一种物质的酰基衍生物在制备用于治疗(包括预防)AIDS相关的疾病的药物中的应用,所述分子式(A)为:
Figure C9619379300031
4.按权利要求1~3中任何一项的应用,其中分子式(A)化合物是泛昔洛韦。
5.按权利要求1~4中任何一项的应用,其中分子式(A)化合物或生物前药、或药物上可接受的盐、磷酸酯和/或上述任何一种物质的酰基衍生物与免疫调节剂结合用药。
6.按权利要求5的应用,其中免疫调节剂是干扰素。
CNB961937939A 1995-03-07 1996-03-05 用于治疗人类疱疹-病毒-8的喷昔洛韦(Penciclovir)的应用 Expired - Fee Related CN1138545C (zh)

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AU701739B2 (en) 1999-02-04
ATE254919T1 (de) 2003-12-15
NO974101D0 (no) 1997-09-05
CA2214406A1 (en) 1996-09-12
CN1183722A (zh) 1998-06-03
NO974101L (no) 1997-09-05

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